This application outlines a program of research and research training intended to facilitate the development of a well-trained neurologist and diagnostic neuropathologist on nervous system aging. Having developed a strong interest in neurodegenerative diseases during my clinical neurology residency training, my attention became focused on Alzheimer's Disease (AD) while serving as a neuropathology fellow under the supervision of Dr. Perl. I became familiar with the literature of AD and of nervous system aging, and participated in several limited research projects involving AD. I would like to continue my investigation of AD, and plan to study the cell biology of pathologically altered neurons in aluminum-induced encephalopathy of the rabbit. A major neuropathologic feature of AD is the neurofibrillary tangle (NFT). Two biologic properties which have been described in AD are elevated aluminum concentrations in NFT-containing neurons derived from AD patients, and several neurotransmitter deficits found in the disease. The relationship of this neuropathologic feature and these biologic properties is not known. Although aluminum-containing compounds produce intraneuronal neurofilamentous accumulations in certain mammalian species, the biologic effects of such pathologically altered cells have not been carefully studied. Utilizing two species of animals, one susceptible to aluminum-induced intraneuronal neurofilamentous degeneration (rabbit) and one resistant (rat), I will attempt to link aluminum neurotoxicity with neurotransmitter deficit in neuronal populations in which neurofilamentous degeneration is produced. The techniques of SEM x-ray spectrometry (for detection and distribution of aluminum) and acetycholinesterase histochemistry and substance P immunohistochemistry (for delineation of neurotransmitter function) will be used. In the context of this proposed research I feel that this project will afford me the opportunity to learn several contemporary research techniques applicable to continued study in the areas of aging and neurodegenerative disease.